Work may lead to the invention of latest therapeutic targets.
For the primary time, researchers have recognized “molecular markers” linked to degeneration—detectable adjustments in cells and their gene-regulating networks—which can be widespread throughout a number of sorts of dementia affecting totally different mind areas. Significantly, the UCLA-led examine, revealed within the journal Cell, additionally found markers distinctive to particular types of dementia. These mixed findings may symbolize a serious shift within the seek for causes, therapies, and cures for these situations.
“This work provides new insight into the mechanisms of neurodegeneration and identifies new candidate pathways for the development of therapeutics,” mentioned senior and corresponding writer Daniel Geschwind, MD, PhD, a professor of human genetics, neurology, and psychiatry on the David Geffen School of Medicine at UCLA and director of the Institute for Precision Health at UCLA Health.
Research Approach: Going Beyond Traditional Case-Control Studies
Previous research have centered on a single dysfunction at a time. Called case-control research, they in contrast “diseased” cells with regular ones and sometimes simply centered on one mind area. But on this analysis, the scientists additionally checked out molecular adjustments throughout three totally different types of dementia that may contain “tau pathology,” the buildup of irregular tau protein in susceptible areas that differ throughout issues.
They carried out single-cell genomic evaluation on greater than 1 million cells to establish distinct and shared molecular markers in three associated situations: Alzheimer’s illness, frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). In addition to validating adjustments beforehand noticed in AD, they establish dozens of cell sorts whose adjustments are shared throughout a number of dementias and a number of other cell sorts whose adjustments in illness had been particular to a single dysfunction, lots of which had not been beforehand recognized.
The Role of Brain Regions and Cells in Neurodegeneration
“Different conditions have different patterns of degeneration. We reasoned that comparison across cases from different disorders, in addition to the typical case-control comparison, would be useful to identify shared components of neurodegeneration and to understand cell type-specific changes that underlie all these conditions,” Geschwind mentioned, including that almost all research profile just one mind area – usually the frontal lobe.
“In dementia and neurodegenerative disease more generally, specific brain regions and cells are most vulnerable in each disease. This is what leads to the different symptoms and signs across disorders,” Geschwind mentioned. “Since regional vulnerability is a core feature of the disorders, we reasoned that studying more than one region would give new insights, and that was the case. In addition to identifying shared and distinct molecular markers, we showed how genetic risk relates to these disease-specific pathways that are altered in the brain.” Using this examine design, the investigators discovered 4 genes that marked susceptible neurons throughout all three issues, highlighting pathways that might be used to develop new therapeutic approaches.
First writer Jessica Rexach, MD, PhD, an assistant professor in neurology and neurobehavioral genetics on the David Geffen School of Medicine at UCLA, mentioned this work “profoundly shifted” her perspective on the mechanisms underlying illness susceptibility.
“It is remarkable and humbling to have identified several distinct molecular differences that set apart cells from individuals with one form of dementia from those with closely related diseases. Although these disease-specific differences were among the minority of the changes observed in diseased brains, they were strongly linked to heritability. This surprising finding opens new avenues for understanding why and how certain genes influence the risk of developing one brain disease over another closely related condition.”
Combined, Alzheimer’s, FTD, and PSP have an effect on greater than 28 million individuals worldwide. Although Alzheimer’s has been studied extensively, there isn’t a treatment, and current, permitted drugs solely gradual illness development. There are few scientific trials out there for FTD and PSP.
New Avenues for Therapeutic Development
“We have created an extensive data resource that paves the way for identifying and exploring new therapeutic candidates for neurodegenerative dementias,” Rexach mentioned. “We have pinpointed specific molecules that can now be advanced as potential novel regulators of disease in experimental systems – importantly, grounded in primary human disease data. Additionally, we’ve uncovered unexpected conceptual phenomena that may explain why certain cells exhibit more resilience or vulnerability to disease, and we’re eager to investigate these findings further.”
The researchers:
- Identified distinctive adjustments particular to Alzheimer’s illness and demonstrated that a number of findings in Alzheimer’s had been additionally noticed throughout the opposite issues, figuring out targets for therapeutic growth.
- Found that “cellular resilience programs” – molecular mechanisms that help cells in response to harm – activated or failed in another way, when evaluating the identical cell sorts throughout issues.
- Were stunned to uncover that every of the three issues had adjustments in cells of the first visible cortex – the realm of the mind that processes visible info and which was thought to be unaffected by dementia. In PSP, this discovery revealed beforehand unknown adjustments in mind cells known as astrocytes.
- Identified particular adjustments within the expression of sure tau-related genes and others in PSP. These seem to correlate with the distinctive sample of mind cell degeneration that’s noticed in PSP.
The authors, who will subsequent start experiments to validate the causal nature of their findings, anticipate the examine will encourage related cross-disorder analysis.
“These data show that known risk genes act in specific neuronal and glial states or cell types that differ across related disorders. Moreover, causally associated disease states may be limited to specific cell types and regions,” the Cell article concludes. “This underscores the importance of examining multiple brain regions to understand causal disease pathways at the cellular level, which we show provides a clearer picture of shared and disease-specific aspects of resilience and vulnerability to inform the therapeutic roadmap.”
Reference: “Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics” by Jessica E. Rexach, Yuyan Cheng, Lawrence Chen, Damon Polioudakis, Li-Chun Lin, Vivianne Mitri, Andrew Elkins, Xia Han, Mai Yamakawa, Anna Yin, Daniela Calini, Riki Kawaguchi, Jing Ou, Jerry Huang, Christopher Williams, John Robinson, Stephanie E. Gaus, Salvatore Spina, Edward B. Lee, Lea T. Grinberg, Harry Vinters, John Q. Trojanowski, William W. Seeley, Dheeraj Malhotra and Daniel H. Geschwind, 11 September 2024, Cell.
DOI: 10.1016/j.cell.2024.08.019
Funding for this work was supplied by Roche Pharmaceuticals (D.H.G., D.M.), BrightFocus (D.H.G., J.E.R), Rainwater Charitable Foundation (D.H.G. and W.W.S), NIH grants (Ok08 NS105916 (J.E.R), R01 AG075802 (J.E.R., L.T.G), 5UG3NS104095 (D.H.G)), and John Douglas French Alzheimer’s Foundation (J.E.R.). The UCSF Neurodegenerative Disease Brain Bank is supported by NIH grants AG023501 and AG019724, the Rainwater Charitable Foundation, and the Bluefield Project to Cure bvFTD. The University of Pennsylvania Center for Neurodegenerative Disease Research is supported by NIH grant P01AG066597, P30AG072979 and U19AG062418.
Disclosures: Geschwind has acquired analysis funding from Hoffman-LaRoche for this mission.
(D.H.G. has acquired analysis funding from Hoffman-LaRoche for this mission. D.C. is a full-time worker of F. Hoffmann-La Roche, Basel, Switzerland. During the examine interval, D.M. was a full-time worker of F. Hoffmann-La Roche, Basel, Switzerland, and is presently a full-time worker of Biogen, Cambridge, MA, USA.)
